In an exciting new advancement in neuroscience, researchers from UCLA say they have discovered a mechanism by which lost memories might be able to restored. The findings, published in the journal eLife, offer some hope for patients in the early stages of Alzheimer’s disease, a form of dementia that causes memory loss and overall cognitive decline.

For decades, most neuroscientists have believed that memories are stored at the synapses — the structures that allow electrical or chemical signals to be sent between brain cells, or neurons — which are destroyed by Alzheimer’s disease. But the UCLA researchers say their findings suggest this may not be the case.

By analyzing the learning and memory processes of a marine snail called the Aplysia – which has similar cellular and molecular functions to humans – the team found they were able to restore lost memories in the snails by triggering regrowth of previously destroyed synaptic connections. Their findings were published recently in eLife, a highly regarded open-access online science journal.

“That suggests that the memory is not in the synapses but somewhere else,” says Dr. David Glanzman, senior author of the study, and a professor in the departments of Integrative Biology and Physiology and Neurobiology at UCLA. “We think it’s in the nucleus of the neurons. We haven’t proved that, though.”

To reach their findings, the researchers “trained” the Aplysias to remember a number of mild electric shocks applied to their tail. The snail displays a defensive response to protect its gill from potential harm, and the researchers were especially interested in its withdrawal reflex and the sensory and motor neurons that produce it.

The researchers studied long-term memories in Aplysias, a type of marine animal with whom humans share many of the same molecular and cellular processes involved in memory formation.

By giving the snail several mild electrical shocks on its tail, the researchers were able to enhance the snail’s withdrawal reflex. The enhancement lasts for days after a series of electrical shocks, which reflects the snail’s long-term memory.

As part of the snail’s response to the shock, the hormone serotonin is released in its central nervous system, encouraging the growth of synaptic connections. In turn, long-term memory is a function of the growth of new synaptic connections caused by the serotonin, says Dr. Glanzman.

As long-term memories are formed, the brain creates new proteins that are involved in making new synapses. If that process is disrupted — for example by a concussion or other injury — the proteins may not be synthesized and long-term memories cannot form. (This is why people cannot remember what happened moments before a concussion.)

“If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn’t remember the training,” says Glanzman. “However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later.”

“In other words,” he adds, “once memories are formed, if you temporarily disrupt protein synthesis, it doesn’t affect long-term memory. That’s true in the Aplysia and in human’s brains.” This explains, for instance, why people’s older memories typically survive following a concussion.

Dr. Glanzman’s team found the same mechanism held true when studying the snail’s neurons in a Petri dish. To observe this process, the researchers placed the sensory and motor neurons that mediate the snail’s withdrawal reflex in a Petri dish, where the neurons re-formed the synaptic connections that existed when the neurons were inside the snail’s body.

When serotonin was added to the dish, new synaptic connections formed between the sensory and motor neurons. But if the addition of serotonin was immediately followed by the addition of a substance that inhibits protein synthesis, the new synaptic growth was blocked; long-term memory could not be formed.

It was long thought that memories were stored in the synapse (pictured above) — which are destroyed in Alzheimer’s patients — but these new findings indicate they are stored elsewhere, possibly in the nucleus of the neuron.

The researchers also wanted to understand whether synapses disappeared when memories did. To find out, they counted the number of synapses in the dish and then, 24 hours later, added a protein synthesis inhibitor. One day later, they re-counted the synapses.

What they found was that new synapses had grown and the synaptic connections between the neurons had been strengthened; late treatment with the protein synthesis inhibitor did not disrupt the long-term memory. The phenomenon is extremely similar to what happens in the snail’s nervous system during this type of simple learning, notes Dr. Glanzman.

Next, the scientists added serotonin to a Petri dish containing a sensory neuron and motor neuron, waited 24 hours, and then added another brief pulse of serotonin — which served to remind the neurons of the original training — and immediately afterward add the protein synthesis inhibitor.

This time, they found that synaptic growth and memory were erased. When they re-counted the synapses, they found that the number had reset to the number before the training. This suggests that the “reminder” pulse of serotonin triggered a new round of memory consolidation, and that inhibiting protein synthesis during this “reconsolidation” erased the memory in the neurons, the researchers explain.

If the prevailing wisdom were true — that memories are stored in the synapses — the researchers should have found that the lost synapses were the same ones that had grown in response to the serotonin. But that’s not what happened: Instead, they found that some of the new synapses were still present and some were gone, and that some of the original ones were gone, too.

Dr. Glanzman says there was no obvious pattern to which synapses stayed and which disappeared, which also implies that memory is not stored in synapses.

‘As long as the neurons are still alive, the memory will still be there’

When the scientists repeated the experiment in the snail, and then gave the animal a modest number of tail shocks — which do not produce long-term memory in a naive snail — the memory they thought had been completely erased returned. This implies that synaptic connections that were lost were apparently restored.

Based on these findings, the researchers say it looks to be possible to restore lost memories in Alzheimer’s patients as long as the neurons are still alive.

“Long-term memory is not stored at the synapse,” says Dr. Glanzman. “That’s a radical idea, but that’s where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won’t be easy, but I believe it’s possible.”

Dr. Glanzman says the research could have significant implications for people with Alzheimer’s disease. Specifically, just because the disease is known to destroy synapses in the brain doesn’t mean that memories are destroyed.

“As long as the neurons are still alive, the memory will still be there, which means you may be able to recover some of the lost memories in the early stages of Alzheimer’s,” he says. However, in the later stages of the disease — when neurons die — it is unlikely that memories could be recovered, he adds.

The cellular and molecular processes seem to be very similar between the marine snail and humans, even though the snail has approximately 20,000 neurons and humans have about 1 trillion. Neurons each have several thousand synapses.

Based on these findings, Dr Glanzman’s team plans to further investigate the restoration of memories and regrowth of synapses in Aplysias, with the goal of ultimately translating their research into real-life solutions for people with Alzheimer’s disease.